ABSTRACT An overarching challenge in breast cancer oncology is the urgency to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and improve the rates of survival. Recent years have seen exponential interest in tumor-derived exosomes; nano-sized (30-150 nm) vesicles shed in large quantities by tumor cells and laden with oncogenic cargo from their parent tumor cell. Research studies have shown that breast cancer cells produce copious quantities of exosomes that are released systemically and mediate tumor- associated immune suppression, resistance to therapies, tissue invasion, and metastasis. Breast cancer exosomes express oncoproteins on their surfaces that have been shown to exert direct actions in interfering with the activity of therapeutic monoclonal antibodies, and countering chemotherapeutic agents. These lines of evidence strongly support the development of strategies to limit the effects of tumor-derived exosomes, however, no such targeted therapeutic strategy exists. The proposed research entails an ex vivo evaluation of a medical device, the Hemopurifier, as a strategy for the capture and removal of exosomes from the plasma of breast cancer patients. The clinical-grade Hemopurifier comprises an extracorporeal hemodialysis cartridge containing a lectin (Galanthus nivalis agglutinin; GNA) affinity matrix. Aethlon has successfully completed an FDA-approved feasibility study using the Hemopurifier for addressing infectious viruses, which have similar sizes and glycosylation signatures as cancer exosomes. Aethlon has also received an Expedited Access Pathway (EAP) designation from the FDA to support the advancement of the Hemopurifier to treat life-threatening viruses. For this prospective new indication for use of the device, our central hypothesis is that the Hemopurifier can be used to target breast cancer exosomes by capturing and removing these vesicles from plasma. In this study, exosomes originating from triple negative and HER2-overexpressing breast cancer cells will be used as a model since research studies have defined the functions of these vesicles in immunosuppression and promoting tumor growth. The proposed proof of concept studies will provide insight into whether exosomes targeted by the Hemopurifier possess signatures and functions that are disease-relevant. We envision that an extracorporeal approach for removing disease-mediating exosomes from circulation may replace or reduce the need for toxic drugs or unmask their efficacy, conceivably serving as an adjunct to standard of care breast cancer treatments.